Ilaria Pezzini

Syndromes associated with mitochondrial DNA depletion

Mitochondrial dysfunction accounts for a large group of inherited metabolic disorders most of which are due to a dysfunctional mitochondrial respiratory chain (MRC) and, consequently, deficient energy production. MRC function depends on the coordinated expression of both nuclear (nDNA) and mitochondrial (mtDNA) genomes. Thus, mitochondrial diseases can be caused by genetic defects in either the mitochondrial or the nuclear genome, or in the cross-talk between the two. This impaired cross-talk gives rise to so-called nuclear-mitochondrial intergenomic communication disorders, which result in loss or instability of the mitochondrial genome and, in turn, impaired maintenance of qualitative and quantitative mtDNA integrity. In children, most MRC disorders are associated with nuclear gene defects rather than alterations in the mtDNA itself.The mitochondrial DNA depletion syndromes (MDSs) are a clinically heterogeneous group of disorders with an autosomal recessive pattern of transmission that have onset in infancy or early childhood and are characterized by a reduced number of copies of mtDNA in affected tissues and organs. The MDSs can be divided into least four clinical presentations: hepatocerebral, myopathic, encephalomyopathic and neurogastrointestinal. The focus of this review is to offer an overview of these syndromes, listing the clinical phenotypes, together with their relative frequency, mutational spectrum, and possible insights for improving diagnostic strategies.

TMEM5-associated dystroglycanopathy presenting with CMD and mild limb-girdle muscle involvement

Highlights • We studied a CMD patient with structural brain abnormalities.• Next-generation sequencing identified a reported variant in TMEM5.• We expanded the spectrum of TMEM5-associated disorders.

Mitochondria and neurodegenerative diseases: the promising role of nanotechnology in targeted drug delivery

ABSTRACT Introduction: Neurodegenerative diseases (NDs) represent a group of different clinical entities that, despite the specific primary etiologies, share a common signature in terms of a general mitochondrial dysfunction with consequent oxidative stress accumulation. As these two events occur early during neurodegenerative process, they could be considered ideal therapeutic targets. Areas covered: This review describes the nanotechnologies explored for the specific targeted delivery of drugs, in order to precisely direct molecules into the intended site, where they can practice their therapeutic effects. Expert opinion: Conventional drug delivery systems cannot provide adequate restoration and connection patterns that are essential for a functional recovery in NDs. Since orally delivered antioxidants are easily destroyed by acids and enzymes, only a small portion of consumed antioxidants gets absorbed, leading to low bioavailability and low concentration at the target site. In this scenario, the identification of new proenergetic drugs, in combination with the development of methods for selectively delivering biologically active molecules into mitochondria, will potentially launch new therapeutic approaches for the treatment of NDs, where energetic imbalance plays a central role.

Cerium oxide nanoparticles: the regenerative redox machine in bioenergetic imbalance

AIM Owing to their catalytic properties as reactive oxygen species scavengers, cerium oxide nanoparticles (nanoceria) have become an extremely promising candidate for medical applications, especially in the treatment of diseases where oxidative stress has been proposed as one of the main pathogenesis factors. MATERIALS & METHODS In this work, nanoceria antioxidant power has been tested in primary cultured skin fibroblasts, derived from healthy individuals, by evaluating the mitochondrial function both in basal condition and after an oxidative insult. RESULTS & CONCLUSION Combined with a clear lack of toxicity, antioxidant activity makes nanoceria promising in a wide range of clinical applications sharing the common signature of a global bioenergetic dysfunction.

Additive effect of nuclear and mitochondrial mutations in a patient with mitochondrial encephalomyopathy

We describe the case of a woman in whom combination of a mitochondrial (MT-CYB) and a nuclear (SDHB) mutation was associated with clinical and metabolic features suggestive of a mitochondrial disorder. The mutations impaired overall energy metabolism in the patients muscle and fibroblasts and increased cellular susceptibility to oxidative stress. To clarify the contribution of each mutation to the phenotype, mutant yeast strains were generated. A significant defect in strains carrying the Sdh2 mutation, either alone or in combination with the cytb variant, was observed. Our data suggest that the SDHB mutation was causative of the mitochondrial disorder in our patient with a possible cumulative contribution of the MT-CYB variant. To our knowledge, this is the first association of bi-genomic variants in the mtDNA and in a nuclear gene encoding a subunit of complex II.

Isolated Mild Intellectual Disability Expands the Aminoacylase 1 Phenotype Spectrum

Aminoacylase 1 (ACY1) deficiency is a rare inborn error of metabolism presenting with heterogeneous neurological symptoms such as psychomotor delay, seizures, intellectual disability and it is characterized by increased urinary excretion of N-acetylated amino acids. We report on a new patient who presented ACY1 deficiency in association with isolated mild intellectual disability, but neither neurological symptoms nor autistic features. The child showed a compound heterozygous mutation (p.Glu233Asp) and a novel p.Ser192Arg fs*64, predicting an unstable transcript and resulting in very low protein levels.This new ACY1 deficient child was identified through regular screening for inborn error of metabolism adopted in our department in all cases of intellectual disability. This report supports a recommendation to perform metabolic investigations in patients with isolated mild intellectual disability.

Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study

BackgroundDystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been associated with α-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes.We re-sequenced the full set of known disease genes in 73 Italian patients with evidence of either reduced or nearly absent α-dystroglycan to assess genotype-phenotype correlations in this cohort. We used innovative bioinformatic tools to calculate the effects of all described GMPPB mutations on protein function and attempted to correlate them with phenotypic expressions.ResultsWe identified 13 additional cases from 12 families and defined seven novel mutations. Patients displayed variable phenotypes including less typical pictures, ranging from asymptomatic hyperCKemia, to arthrogryposis and congenital clubfoot at birth, and also showed neurodevelopmental comorbidities, such as seizures and ataxic gait, as well as autism-spectrum disorder, which is seldom described in clinical reports of dystroglycanopathies. We also demonstrated that few mutations recur in the Italian GMPPB-mutated population and that alterations of protein stability are the main effects of GMPPB missense variants.ConclusionThis work adds to the data on genotype-phenotype correlations in α-DG and offers new bionformatic tools to provide the conceptual framework needed to understand the complexity of these disorders.

Smart inorganic nanoparticles for wireless cell stimulation

Abstract New nanotechnological tools able to remotely and noninvasively modulate cell behaviors have been recently developed and characterized. In this chapter, we focus on the most exciting and innovative studies where different typologies of active inorganic nanomaterials have been adopted to promote cell activity, maturation, and function. In particular, the effects of near-infrared absorbing gold nanoparticles and piezoelectric nanotransducers on the modulation of biological activity are reviewed.

Modulation of gene expression in rat muscle cells following treatment with nanoceria in different gravity regimes

AIM Oxidative stress (OS) is strictly associated with senescence/pathogenesis of biological systems. As putative countermeasure to environmental OS, cerium oxide nanoparticles (nanoceria [NC]) were administered to muscle cells on ground and aboard the International Space Station. MATERIALS & METHODS Transcriptional analyses were conducted through microarray technology and hierarchical clustering. Venn diagram and gene ontology analyses were also performed on selected gene lists. RESULTS Adaptive responses to both NC administration and to permanence in real microgravity conditions occurred. Enrichment in the biological processes related to aging, body fat development and mesodermal tissue proliferation for NC-treated samples were found. CONCLUSION Nanotechnology antioxidants promise applications to pathological conditions governed by OS on Earth and in life-hostile environments (low Earth orbit and deep space).